Airway remodeling in asthma is a process of permanent structural changes occurring over time,[unreadable] resulting in a component of fixed airway obstruction that can lead to reduced lung function. We have shown[unreadable] that airway inflammation occurs in both the proximal and distal lung in asthma and that collagen expression[unreadable] is increased and airway elastin expression is reduced. The mechanisms by which Th2 inflammation leads to[unreadable] the subsequent host response of remodeling are poorly understood. Interleukin (IL)-13, a Th2 cytokine[unreadable] critical to the asthma phenotype in murine models, also causes fibrosis by effects on the airway fibroblast. A[unreadable] mediator induced by IL-13 that links inflammation to the structural changes in the proximal and distal lung is[unreadable] platelet-derived growth factor (PDGF) a potent chemoattractant and mitogen for fibroblasts. PDGF isoforms[unreadable] and receptors are expressed in the lung, induced by IL-13 and expression is inceased by corticosteroids in[unreadable] animal models. We hypothesize that interleukin-13 modulates airway fibroblast function in human[unreadable] asthma via increased expression of platelet-derived growth factor and subsequent airway fibroblast[unreadable] proliferation, collagen expression and decreased elastin expression. Corticosteroids, the mainstay of[unreadable] therapy for asthma, do not suppress and may enhance these processes. These processes result in a[unreadable] reduction in lung function, airway collapsibility and loss of elastic recoil. Corticosteroids, the mainstay of[unreadable] therapy for asthma, do not suppress and may enhance these processes.To test this hypothesis, subjects[unreadable] with mild and severe asthma and normal controls will undergo bronchoscopy with proximal (endobronchial)[unreadable] and distal (transbronchial) lung biopsy (asthmatic subjects only) and bronchoalveolar lavage. We will first[unreadable] determine that IL-13 induces PDGF expression by the airway fibroblast in human asthma, and that this[unreadable] requires activation of STAT-6 and Egr-1 (specific aim 1). In specific aim 2, we will determine that PDGF[unreadable] modulates fibroblast collagen and elastin expression throughout the lung via activation of PIS kinase. In[unreadable] specific aim 3, we will determine that neutralization of IL-13 in vivo will result in improved lung function and[unreadable] decreased PDGF and airway fibroblast activation ex vivo. We will relate the pathologic airway changes and[unreadable] ex vivo fibroblast function to measures of large and small airway function in asthmatic human subjects in[unreadable] vivo in hopes of predicting in the laboratory who will suffer the greatest physiological consequences of airway[unreadable] remodeling. This proposal will shed light on the physiologic and pathologic consequences of airway[unreadable] remodeling in asthma, the host response to Th2 inflammation that lead to remodeling and whether our main[unreadable] therapy for asthma, corticosteroids, modulate and possibly enhance this process. This project will evaluate[unreadable] host responses leading to airway remodeling in asthma in conjunction with projects 1 and 4, provide human[unreadable] samples for projects 1 and 4 and interact with all the Cores.